1. Field of the Invention
The present invention relates generally to the field of glaucoma and, more specifically, to the use of inhibitors of Jun N-terminal kinases (JNK) to lower intraocular pressure and provide neuroprotection to patients suffering from glaucoma.
2. Description of the Related Art
Many pathological changes in the eye, such as glaucoma, acute ischemic optic neuropathy, macular degeneration, retinitis pigmentosa, retinal detachment, retinal tears or holes, and other ischemic retinopathies or optic neuropathies, cause injury or death of retinal neurons, which can lead to loss of vision. For example, primary open-angle glaucoma (POAG) is a progressive disease leading to optic nerve damage and ultimately blindness. The cause of this disease has been the subject of extensive studies for many years, but is still not fully understood. Glaucoma results in the neuronal degeneration of the retina and optic nerve. Even under optimal medical care and surgical treatment, it is still associated with a gradual loss of retinal ganglion cells (RGC), which causes a decline of visual function (Van Buskirk et al. (1993); Schumer et al. (1994)).
An abnormal increase in intraocular pressure (IOP) is a major risk factor of glaucoma. Currently, the only available treatment for glaucoma is to lower IOP either by medication or surgery. Lowering IOP is effective in slowing the development of POAG and delaying its damaging effects. Nonetheless, the loss of visual field in glaucoma patients does not always correlate with IOP, and lowering IOP alone does not completely stop the disease process.
There is not one mechanism that seems sufficient alone to explain the wide spectrum and patterns of pathological changes usually observed in glaucoma patients. It is probable that glaucoma involves more than one etiology and different mechanisms are manifested in different patients and/or different stages of the disease. Some of the more important proposals are: deprivation of neurotrophic factors, vascular abnormality (ischemia), and glutamate toxicity. These mechanisms eventually lead to apoptosis of the RGC (Clark & Pang (2002)).
The same mechanisms have been proposed to be involved in other ocular diseases. For example, a decrease in neurotrophic factors is associated with a rat model of retinitis pigmentosa (Amendóla et al. (2003)). Introduction of certain neurotrophic factors to the retina can reduce retinal damages related to retinitis pigmentosa (Tao et al. (2002)), retinal detachment (Hisatomi et al., (2002); Lewis et al. (1999)), and experimental macular degeneration (Yamada et al. (2001)). Retinal ischemia is involved in acute ischemic optic neuropathy, macular degeneration (Harris et al. (1999)), and other ischemic retinopathies or optic neuropathies. Similarly, glutamate toxicity may contribute to the retinal damages seen in retinal detachment (Sherry & Townes-Anderson (2000)).
U.S. Patent Application No. US2005/0069893 describes the measurement of JNK gene expression as a means of diagnosing glaucoma but does not discuss the use of inhibitors of JNK to lower intraocular pressure or to provide neuroprotection to a patient suffering from glaucoma.
Currently, no available therapy for glaucoma seeks to interrupt the mechanisms by which the ocular tissues are damaged in the disease process. Moreover, although a variety of therapeutic agents have been proposed as having the ability to lower ocular hypertension, many of these agents have associated side effects which may render them undesirable as ocular therapeutic agents. What is needed is a glaucoma treatment that addresses the underlying pathological cause of the disease and thereby provides a decrease in IOP and neuroprotection without resulting undesirable side effects typically associated with agents used to lower IOP.